KCNH2 Variant G601S Detail

We estimate the penetrance of LQTS for KCNH2 G601S is 67%. This variant was found in a total of 23 carriers in 10 papers or gnomAD, 16 had LQTS. G601S is not present in gnomAD. G601S has been functionally characterized in 9 papers. This residue is located in a Hotspot region for LQT2. In silico predictions, functional data (if available), and location in structure are equivalent to observing 6 individuals with LQT2 and 4 unaffected individuals.These data combined with observations of carriers lead us to estimate the LQTS penetrance for KCNQ1 G601S around 67% (22/33).

In Silico Data

PROVEAN PolyPhen-2 BLAST-PSSM REVEL Penetrance Density (%)
-0.071 0.125 1 0.631 71
PROVEAN scores less than -2 are considered deleterious. REVEL scores higher than 0.5 or 0.75 are considered likely pathogenic (higher sensitivity with the former cutoff, higher specificity with the latter cutoff). A PolyPhen-2 score of 0.85 or greater is considered likely pathogenic. BLAST-PSSM reflects the evolutionary conservation of residue substitutions, more negative numbers indicate fewer observations of the specific substitution than is expected. Penetrance density is our previously published method to calculate the average LQTS probability density in a shell of residues surrounding a residue of interest (Kroncke et al. 2019).

Reported Carrier Data

PubMed ID Year Carriers Unaffected LQT2 Other Disease
16969682 2006 4 0 4
Japan Cohort 2020 6 2 4
19169982 2008 1 0 1 Seizures
Italy Cohort 2020 3 2 1
France Cohort 2020 2 1 1
23864605 2013 9 0
9452080 1998 3 0 3
10862094 2000 3 2 1
26496715 2015 2 0 2
29622001 2018 2 0 2
LITERATURE, COHORT, AND GNOMAD: - 23 7 16 -
VARIANT FEATURES ALONE: - 10 4 6 -
Summary totals might not agree with the literature table because of duplicate patients, which were excluded from the total counts. We do not distinguish here between multiple missense codons. Missense variants are combined across degenerate codon substitutions since codon-level data were not consistently available for curation.

Functional Data Homozygously Collected

Steady state (S.S.) and peak tail current are relative % to wildtype (100% being no different from wildtype). V0.5 act/inact are the voltages at which half of the maximal current is reached during an activation and inactivation protocol, each is in units of mV and relative to wildtype. Recovery from inactivation (Rec. inact.) and deactivation time (Deactivation) are the ratio of characteristic time constants with wildtype (unitless).

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Recov. Inact. Deactivation (%WT)
10226095 Xeno 63 0.85 -2.72 None None
10226095 HEK293 16 0.9 None None None
11741928 HEK293 15 None None None None
12070109 HEK293 None None None None
12837749 HEK293 5 None None None None
15851652 HEK293 26 None None None None
16432067 HEK293 25 None None None None
20363883 murine 0.2 None None None
23864605 HEK293 None None None None

Functional Data Heterozygously Collected

Functional parameters are the same as defined above.

PubMed ID Cell Type S.S Peak (%WT) Peak Tail IKr (%WT) V1/2 Act. V1/2 Inact. Deactivation (%WT)
10226095 Xeno 90 None None None
10226095 HEK293 None None None
11741928 HEK293 None None None
12070109 HEK293 None None None
12837749 HEK293 None None None
15851652 HEK293 None None None
16432067 HEK293 55 None None None
20363883 murine None None None
23864605 HEK293 None None None

G601S has 31 previously observed neighbors within 15 angstroms

A residue within a folded protein on average has nearest neighbors that fall roughly into two shells: a "nearest" neighbor around 5-6 angstroms and a second shell around 11 angstroms. NOTE: some residues appear multiple times at different distances since the functional KV11.1 channel (protein product of KCNH2/hERG) is a homotetramer and occasionally the same residue from multiple subunits is present within the 15A window. All variants shown in the rightmost column have been observed in at least one individual in the literature or gnomAD.

Neighbor Distance (Angstroms) Variants Observed in Individuals
601 0 G601S,
600 4
602 4 L602X,
599 5 S599N,
603 5 G603D,
598 7
604 7 G604S, G604D, G604C,
597 8 Y597H, Y597C,
605 8 P605L,
596 8 P596L, P596S, P596T, P596R,
606 8 S606P, S606F, S606Del,
595 9 K595N, K595E, K595N,
607 9
594 10
608 10
593 11 I593X, I593V, I593R, I593K, I593T,
609 11 D609N, D609G,
592 11 Q592X,
610 11
591 12 D591N, D591H,
611 12 Y611D,
590 13 G590D, G590V,
612 13 V612L, V612A, V612L,
589 13 L589P,
613 13 T613A, T613L, T613K, T613M,
588 14 N588K, N588K, N588D,
614 14 A614T, A614V,
587 14
615 14 L615V, L615F,
586 15 L586M,
616 15 Y616S,